Leflunomide analogs for treating rheumatoid arthritis

ABSTRACT

Novel leflunomide analogs were synthesized and evaluated in-vivo. Based on the in-vivo studies, these analogs are surprisingly effective for treating rheumatoid arthritis.

BACKGROUND

Rheumatoid arthritis (hereinafter referred to as RA) is a chronicdisease that inflames joints and nearby areas. Besides the joints, othertissues can also be affected by RA. Patients with RA usually haveoverreactive T cells. Therefore, RA can be categorized as an autoimmunedisease.

Leflunomide,N-(4-trifluoromethylphenyl)-4-carboxamidyl-5-methylisoxazole, is a drugfor treating RA introduced into the market in recent years. Leflunomideand its main metabolite, malononitrilamide (MNA), were first made byHoechst Marion Roussel.

OBJECTIVES

The objectives of this invention are as follows:

1. To synthesize a series of novel analogs of leflunomide,

2. To conduct in-vivo studies to evaluate the efficacy of the analogs,and

3. To select the leflunomide analogs that can be used for treatingrheumatoid arthritis.

DETAILED DESCRIPTION OF THE INVENTION

This invention comprises the syntheses of a series of novel analogs ofleflunomide for treating Rheumatoid Arthritis. To the best of ourknowledge, these analogs have not been disclosed by any other parties.The in-vivo animal studies indicate that these leflunomide analogs aresurpassingly more effective than leflunomide.

Representative syntheses and in-vivo animal studies are described asfollows:

A. Methods of Syntheses

Wherein DCC is N,N′-dicyclohexylcarbodiimide and TEA is triethylamine.

Analog 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k R 4-H 2-Cl 3-Cl 4-Cl 3-CF₃ 4-CF₃2,4-(Cl)₂ 4-OCH₃ 3,4,5-(OCH₃)₃ 4-COOH 4-F

Method 1:

Weigh 1 g of 5-methylisoxazole-3-carboxylic acid; dissolve it in 10 mLof chloroform in a reactor. Place the reactor in an ice bath and add 1.2mL of thionyl chloride. Gradually add 1 mL of triethylamine. Reduce thevolume under vacuum after the reaction is complete. Add dichloromethane(10 mL) and then add the desired substituted aniline (see the tableabove) and mix thoroughly with cooling from an ice bath. Addtriethylamine (1 mL), let it react for about 30 minutes, and monitor thereaction by thin layer chromatography. Wait till the reaction iscomplete and concentrate under vacuum. Use a separatory funnel toseparate the organic and aqueous layers. Keep the organic layer; addanhydrous magnesium sulfate; let it sit for about 30 minutes; filter offmagnesium sulfate and keep the filtered organic liquid; dry the organicliquid to obtain the crude product; re-crystallize in absolute alcoholto obtain product 5 a and 5 b.

Aniline Yield Product mL g (%) Appearance 5a 1.1 0.1 (4.2) Yellowcrystals 5b 1 0.1 (7.2) Off-white crystals

Method 2:

Weigh 5-methylisoxazole-3-carboxylic acid (2 g), N-hydroxysuccinimide (2g) and coupling agent N,N′-dicyclohexylcarbodiimide (3.6 g); add thedesired substituted aniline, and crystallize in absolute alcohol to make5 a˜5 k.

Anilines Yield Product mL g (%) Appearance 5a 2 mL 1.0 (71) Yellowcrystals 5b 2 mL 0.9 (20.2) Off-white crystals 5c 2 mL 2.4 (53.8) Whitecrystals 5d 2.4 g 8.7 (45) White crystals 5e 2 mL 3.8 (89.1) Whitecrystals 5f 2 mL 1.6 (37) White crystals 5g 3.4 g 4.2 (73.2) Off-whitecrystals 5h 2.1 g 0.76 (18.9) Gray crystals 5i 3.2 g 2 (39.6) Graycrystals 5j 2.4 g 1.9 (44.6) Light-brown crystals 5k 2 mL 0.9 (21.6)White crystals

B. Results of Syntheses

Results of the syntheses and characteristics of the leflunomide analogsare shown as follows:

[Compound 5 a] N-(Phenyl)-3-carboxamidyl-5-methylisoxazole

mp: 109˜110° C.; UV (MeOH): λ_(max)nm (log ε)=270 (4.025); IR (KBr):νcm⁻¹=3339 (N—H), 1677(C═O), 1598 (C═C); MS (EI, 70ev): 202 (M⁺, 100),119 (65); ¹H-NMR (DMSO-d₆, −300 MHz): δ(ppm); 2.47 (3H, s, CH₃), 6.65(1H, s, CCH), 7.11 (1H, t, J=6.6 Hz, H₄-phenyl), 7.34 (2H, t, J=7.5 Hz,H_(3,5)-phenyl), 7.80 (2H, d, J=9 Hz, H_(2,6)-phenyl), 10.64 (1H, s,NH); ¹³C-NMR (DMSO-d₆, 75 MHz): δ(ppm); 12.1, 101.9, 120.9, 124.6,129.0, 138.4, 157.8, 159.6, 171.7; CHN Analysis (Theory/Experiment)based on C₁₁H₁₀N₂O₂; % C; (65.34/65.28), % H; (4.98/4.95), % N;(13.85/13.72).

[Compound 5 b] N-(2-Chlorophenyl)-3-carboxamidyl-5-methylisoxazole)

mp: 90˜92° C.; UV (MeOH): λ_(max)nm (log ε)=250 (3.33); IR (KBr):νcm⁻¹=3326 (N—H), 1626 (C═O), 1575 (C═C); MS (EI, 70ev): 236 (M⁺), 201(100), 173 (60); ¹H-NMR (DMSO-d₆, −300 MHz): δ(ppm); 2.50 (3H, s, CH₃),6.69 (1H, s, CCH), 7.29 (1H, t, J=7.7 Hz, H₄-phenyl), 7.39 (1H, t, J=7.7Hz, H₅-phenyl), 7.55 (1H, d, J=7.8 Hz, H₃-phenyl), 7.71 (1H, d, J=7.9Hz, H₆-phenyl), 10.19 (1H, s, NH); ¹³C-NMR (DMSO-d₆, 75 MHz): δ(ppm);12.24, 101.8, 127.1, 128.0, 129.9, 134.2, 157.7, 158.9, 172.2; CHNAnalysis (Theory/Experiment) based on C₁₁H₉ClN₂O₂. % C; (55.83/55.36), %H; (3.83/3.77), % N; (11.84/11.99).

[Compound 5 c] N-(3-Chlorophenyl)-3-carboxamidyl-5-methylisoxazole

mp: 91˜93° C.; UV (MeOH): λ_(max)nm (log ε)=260 (4.01); IR (KBr):νcm⁻¹=3347 (N—H), 1689 (C═O), 1593 (C═C); MS (EI, 70ev): 236 (M⁺), 173(100), 153 (80); ¹H-NMR (DMSO-d₆, −300 MHz): δ(ppm); 2.49 (3H, s, CH₃),6.66 (1H, s, CCH), 7.18 (1H, d, J=8 Hz, H₄-phenyl), 7.37 (1H, t, J=8.1Hz, H₅-phenyl), 7.72 (1H, d, J=8.3 Hz, H₆-phenyl), 7.94 (1H, s,H₂-phenyl), 10.82 (1H, s, NH); ¹³C-NMR (DMSO-₆, 75 MHz): δ(ppm); 12.2,120.0, 119.2, 120.3, 124.3, 130.7,133.3, 139.9,.158.0, 159.3, 171.9; CHNAnalysis (Theory/Experiment) based on C₁₁H₉ClN₂O₂; % C; (55.83/55.93), %H; (3.83/3.75), % N; (11.84/11.84).

[Compound 5 d] N-(4-Chlorophenyl)-3carboxamidyl-5-methyisoxazole

mp: 135˜140° C.; UV (MeOH): λ_(max)nm (log ε)=234 (4.55), 269 (4.74); IR(KBr): νcm⁻¹=3329 (N—H), 1683 (C═O), 1528 (C═C); MS (EI, 70ev): 236(100), 201(M⁺); ¹H-NMR (DMSO-d₆, −300 MHz): δ(ppm); 2.50 (3H, S, CH₃),6.68 (1H, s, CCH), 7.71 (2H, d, J=8.1 Hz, H_(3,5)-phenyl), 8.02 (2H, d,J=7.8 Hz, H_(2,6)-phenyl), 10.98 (1H, s, NH); ¹³C-NMR (DMSO-₆, 75 MHz):δ(ppm); 12.1, 101.9, 122.4, 128.4, 128.9, 137.4, 157.9, 159.4, 171.7;CHN Analysis (Theory/Experiment) based on C₁₁H₉ClN₂O₂; % C;(55.83/55.93), % H; (3.83/3.98), % N; (11.84/11.17)

[Compound 5 e] N-(3-Trifluoromethyl)-3-carboxamidyl-5-methylisoxazole

mp: 156˜158° C.; UV (MeOH): λ_(max)nm (log ε)=255 (4.098); IR (KBr):3330 (N—H), 1683 (C═O), 1557 (C═C); MS (EI, 70ev): 271 (M⁺, 90), 102(100); ¹H-NMR (DMSO-d₆, −300 MHz): δ(ppm); 2.49 (3H, s, CH₃), 6.68 (1H,s, CCH), 7.47 (1H, d, J=7.3 Hz, H₄-phenyl), 7.57 (1H, t, J=7.9 Hz,H₅-phenyl), 8.04 (1H, d, J=8.1 Hz, H₆-phenyl), 8.26 (1H, s, H₂-phenyl),10.99 (1H, s,NH); ¹³C-NMR (DMSO-d₆, 75 MHz): δ(ppm); 12.2, 101.9, 117.0,117.1, 120.9, 124.5, 130.1, 130.3, 139.3, 158.2, 159.3, 171.9; CHNAnalysis (Theory/Experiment) based on C₁₂H₉F₃N₂O₂; % C; (53.34/53.39), %H; (3.36/3.59), % N; (10.37/10.71).

[Compound 5 f]N-(4-Trifluoromethylphenyl)3-carboxamidyl-5-methylisoxazole

mp 179˜180° C.; UV (MeOH): λ_(max)nm (log ε)=268 (3.887); IR (KBr):νcm⁻¹=3334 (N—H), 1677(C═O), 1539 (C═C); MS (EI, 70ev): 270 (M⁺, 100);¹H-NMR (DMSO-d₆, −300 MHz): δ(ppm); 2.49 (3H, s, CH₃), 6.68 (1H, s,CCH), 7.71 (2H, d, J=8 Hz, H_(2,6)-phenyl), 8.03 (2H, d, J=8.2 Hz,H_(3,5)-phenyl), 10.99 (1H, s, NH); ¹³C-NMR (DMSO-d₆, 75 MHz): δ(ppm);12.1, 101.9, 122.4, 128.4, 128.9, 137.4, 157.8, 159.4, 171.7; CHNAnalysis (Theory/Experiment) based on C₁₂H₉F₃N₂O₂; % C; (53.34/53.01), %H; (3.36/3.46), % N; (10.37/10.38).

[Compound 5 g] N-(2,4-Dichlorophenyl)-3carboxamidyl-5-methylisoxazole

mp: 148˜156° C.; UV (MeOH): λ_(max)nm (log ε)=250 (4.89), 277 (3.88); IR(KBr): νcm⁻¹=3348 (N—H), 1697 (C═O), 1589 (C═C) MS (EI, 70ev): 271(100), 154(M⁺); ¹H-NMR (DMSO-d₆, −300 MHz): δ(ppm); 2.50 (3H, s, CH₃),6.67 (1H, s, CCH), 7.41 (1H, d, J=8.7 Hz H₅-phenyl), 7.66 (1H, d, J=2.2Hz, H₃-phenyl, 7.83 (1H, d, J=8.7 Hz, H₆-phenyl), 10.25 (1H, s, NH); CHNAnalysis (Theory/Experiment) based on C₁₁H₈Cl₂N₂O₂; % C; (48.73/48.14),% H; (2.97/2.97), % N; (10.33/10.35).

[Compound 5 h] N-(4-Methoxyphenyl)-3carboxamidyl-5-methylisoxazole

mp: 124˜126° C.; UV (MeOH): λ_(max)nm (log ε)=227 (3.76), 288 (3.69); IR(KBr): νcm⁻¹=3332 (N—H), 1672 (C═O), 1521 (C═C); MS (EI, 70ev): 232 (M⁺,100), 149 (64); ¹H-NMR (DMSO-d₆, −300 MHz): δ(ppm); 2.48 (3H, s, CH₃),3.73 (3H, s, OCH₃), 6.63 (1H, s, CH₃), 6.91 (2H, d, J=8 Hz,H_(3,5)-phenyl), 7.69 (2H, d, J=8.1 Hz, H_(2,6)-phenyl), 10.52 (1H, s,NH); ¹³C-NMR (DMSO-d₆, 75 MHz): δ(ppm); 10 12.2, 55.5, 101.9, 114.1,122.3, 122.4, 131.5, 156.3, 157.4, 159.7, 171.6; CHN Analysis(Theory/Experiment) based on C₁₁H₁₂N₂O₃; % C; (62.06/62.12), % H;(5.21/5.23), % N; (12.06/12.33);

[Compound 5 i]N-(3,4,5-Trimethoxyphenyl)-3-carboxamidyl-5-methylisoxazole

mp: 170˜172° C.; UV (MeOH): λ_(max)nm (log ε)=293 (3.439); IR (KBr):νcm⁻¹=3326 (N—H), 1688 (C═O), 1557 (C═C); MS (EI, 70ev): 292 (M⁺, 100),277 (20); ¹H-NMR (DMSO-d₆, −300 MHz): δ(ppm); 2.49 (3H, s, CH₃), 3.63(6H, s, 2OCH₃), 3.75 (3H, s, OCH₃), 6.35 (1H, s, CCH₃), 7.25 (2H, s,H_(2,6)-phenyl), 10.52 (1H, s, NH); CHN Analysis (Theory/Experiment)based on C₁₁H₁₂N₂O₃; % C; (57.53/57.65), % H; (5.52/5.61), % N;(9.58/9.59).

[Compound 5 j] 4-[(5-Methylisoxazole-3-carbonyl)-amino]-benzoic acid

mp: 267˜270° C.; UV (MeOH ): mλ_(max)nm (log ε)=284 (4.27); IR (KBr):νcm⁻¹=3342 (N—H), 1685 (C═O), 1529 (C═C); MS (FAB): m/z 247 (MH⁺);¹H-NMR (DMSO-d₆, −300 MHz): δ(ppm); 2.50 (3H, s, CH₃), 6.69 (1H, s,CCH), 7.94 (4H, s, H_(2,3,5,6)-phenyl), 10.94 (1H, s, NH); ¹³C-NMR(DMSO-d₆, 75 MHz): δ(ppm); 12.2, 102.1, 120.2, 126.6, 130.6, 142.5,158.2, 159.4, 167.2, 171.9; CHN Analysis (Theory/Experiment) based onC₁₁H₉ClN₂O₂; % C; (58.54/58.46), % H; (4.09/4.10), % N; (11.38/11.42).

[Compound 5 k] N-(4-Fluorophenyl)-3-carboxamidyl-5-methylisoxazole

mp: 136˜138° C.; UV (MeOH): λ_(max)nm (log ε)=271 (4.19); IR (KBr):νcm⁻¹=3342 (N—H), 1685 (C═O), 1529 (C═C); MS (EI, 70ev): 220 (M⁺, 100),137 (30), 110 (38); ¹H-NMR (DMSO-d₆, −300 MHz): δ(ppm); 2.49 (3H, s,CH₃), 6.65 (1H, s, CCH), 7.10 (2H, dd, J=5.2, 5.1 Hz, H_(2,6)-phenyl),7.80 (2H, dd, J=8.8, 8.6 Hz, H_(3,5)-phenyl), 10.71 (1H, s, NH); ¹³C-NMR(DMSO-d₆, 75 MHz): δ(ppm); 12.2, 101.9, 115.5, 122.7, 134.7, 157.7,159.5, 160.6, 171.7; CHN Analysis (Theory/Experiment) based onC₁₂H₉FN₂O₂; % C; (60.0/60.17), % H; (4.12/4.17), % N; (12.72/12.47).

C. In-Vivo Experiments

C-1. Animal Used

Wistar Albino Rats of 4 to 6 weeks old with weights of 100-150 g wereused for the studies.

C-2. Preparation of reagents

1.1 % carrageenan solution

Weigh 30 mg of λ-carrageenan (Sigma Chemical) powder; add 3 mL of salineto make the 1% carrageenan solution.

2. CMC (carboxymethyl cellulose) solution

Weigh 30 mg of λ-carrageenan (Sigma Chemical) powder; add 3 mL of salineto make the 1% carrageenan solution.

3. Dexamethasone suspension

Weigh 7.5 mg of dexamethone (Sigma Chemical Co., USA), add 5 mL of 1%CMC solution, shake to make the 1.5 mg/mL dexamethasone suspension.

4. Ibuprofen suspension Weigh 10 mg of ibuprofen (Sigma Chemical Co.,USA), add 10 mL of 1% CMC solution, shake to make the 1 mg/ml ibuprofensuspension.

5. Suspensions of testing compounds

Individually weigh 10 mg of each testing compound; add 10 mL of 1% CMCand shake to make the suspension.

6. Solution used to measure the inflammation

Weigh 0.4-0.5 g of NaCl; add 5 mL of surfactant, Lubricant IMBIBNTEBBC97 (Chimifoto ornano S. P. A. Italy); Add de-ionized water to make 1liter.

C-3. Efficacy and Results

In the present invention, Carrageenan was used to stimulate theinflammation on the rear left footpad of the rat. The inflammation onthe left footpad of each rat was measured for rats with and withouttreatment. Treatment includes leflunomide analogs, dexamethasone,ibuprofen, and Malononitrilamide (MNA). Measurements of the inflamationat pre-determined time points were made.

The rats were weighed and divided into three groups: (1) Control Group,(2) Test Group, and (3) Comparison Group. For each compound, 5 rats wereused and marked on the tails. Before injecting carrageenan, the volumeof each left footpad was measured (V₀). Each rat was injected in theback as follows:

(1) Control Group: 1% CMC for Control Group,

(2) Testing Group: testing compound (10 mg/kg each) in 1% CMC, and

(3) Comparison Group: dexamethasone (1.5 mg/kg in 1% CMC), ibuprofen 10mg/kg in 1% CMC, MNA in 1% CMC.

One hour later, 0.05 mL of 1% carrageenan was injected onto the rearfootpad of each rat to initiate the inflammation. Measure the volume ofthe rear left footpad (V_(t)) at 0.5, 1, 2, 3, 4, and 5 hours.

The Edema Rate (E%) and the Inhibition Rate (I%) are calculated asfollows and the results of the in-vivo studies are summarized in Table 1and Table 2.${E\quad \%} = {\frac{V_{t} - V_{0}}{V_{0}} \times 100\%}$${I\quad \%} = {\frac{E_{c} - E_{t}}{E_{c}} \times 100\%}$

V₀=Volume (mL) of the rear left footpad before the injection ofCarrageenan.

V_(t)=Volume (mL) of the rear left footpad at “t” time after theinjection of Carrageenan

E_(c)=Edema Rate of the, Control Group

E_(t)=Edema Rate of the Testing Group and Comparison Group

TABLE 1 Efficacy of Dexamethasone, ibuprofen, leflunomide, andmalononitrilamide Dose Edema rate^(a) (E%) after carrageenanadministration Groups (mg/kg) 1 hr 2 hr 3 hr 4 hr 5 hr Control 20.8 ±2.9 33.8 ± 1.8 55.3 ± 2.4   63 ± 2.1 64.5 ± 1.8 Dexamethasone 1.5  5.5 ±0.7   12 ± 1.8 18.9 ± 1.5 21.1 ± 0.4 21.7 ± 0.4  (73.6)^(b) (64.5)(65.8) (66.5) (66.4) Ibuprofen 10 18.9 ± 1.1 26.5 ± 1.4 29.9 ± 0.1   35± 0.9 40 ± 0.41 (9.1)  (21.6) (45.9) (44.4) (38) 20 11.5 ± 1.8 19.2 ±0.4 24.5 ± 1.1 28.3 ± 1.5 31.2 ± 1.6 (20.8) (43.2) (55.7) (55.1) (51.6)30  6.2 ± 0.2 10.9 ± 0.6 11.2 ± 0.2 15.8 ± 0.7 30.3 ± 4.2 (65.4) (67.8)(79.7) (74.9) (53)   Leflunomide 5   20 ± 0.9 27.2 ± 0.5 32.6 ± 0.7 38.7± 0.5 39.8 ± 1.2  (3.8) (19.5) (41)   (38.6) (38.3) 10 14.9 ± 1.2 22.2 ±1.2 24.9 ± 2.4 32.9 ± 1.3 34.8 ± 1.4 (28.4) (34.3) (55)   (47.8) (46)  20 11.3 ± 0.8 16.9 ± 1.1 21.9 ± 1.2   25 ± 1.5 27.5 ± 0.9 (45.7) (50)  (60.4) (60.3) (57.4) Malononitrilamide 10 15.2 ± 1.5 17.6 ± 1   20.5 ±0.5 21.7 ± 0.9 24.2 ± 1.3 (MNA) (26.9) (47.9) (63)   (65.6) (62.5)^(a)Each value represents the mean ± S.D. of 5 animals. ^(b)The numberin parentheses indicates the percentage inhibition rate (I %).

TABLE 2

Efficacy of N-(Substituted-phenyl)-3-carboxamidyl-5-methylisoxazolesDose Edema rate^(a) (E%) after carrageenan administration Groups R(mg/kg) 1 hr 2 hr 3 hr 4 hr 5 hr Control 20.8 ± 2.9 33.8 ± 1.8 55.3 ±2.4   63 ± 2.1 64.5 ± 1.8 Leflunomide 10 14.9 ± 1.2 22.2 ± 1.2 24.9 ±2.4 32.9 ± 1.3 34.8 ± 1.4  (28.4)^(b) (34.3) (55)   (47.8) (46)   5a 4-H10  7.8 ± 1.2  8.5 ± 0.3 11.7 ± 0.5 13.6 ± 0.8 35.8 ± 1.4 (62.5) (74.9)(78.8) (78.4) (44.5) 5b 2-Cl 10  4.1 ± 0.4  5.9 ± 0.4 11.4 ± 0.5 13.2 ±1.2 14.4 ± 0.8 (80.1) (82.5) (79.4) (79)   (77.7) 5c 3-Cl 10  7.4 ± 0.715.1 ± 0.8 21.8 ± 1.3 22.8 ± 1.8 25.1 ± 1.3 (64.4) (55.3) (60.6) (63.8)(61.1) 5d 4-Cl 10  6.2 ± 0.7  9.2 ± 0.3 12.4 ± 1.4   14 ± 1.1 15.5 ± 0.6(70.2) (72.8) (77.6) (77.8) (76)   5e 3-CF₃ 10 15.4 ± 0.3 19.7 ± 1.732.8 ± 2.7 35.3 ± 0.9 34.3 ± 3.2 (26)   (41.7) (40.7) (44)   (46.8) 5f4-CF₃ 10 11.2 ± 0.9 15.6 ± 0.4 25.1 ± 0.2 26.2 ± 0.1 26.9 ± 0.5 (46.2)(53.8) (54.6) (58.4) (58.3) 5g 2,4-(Cl)₂ 10  4.3 ± 0.1  5.7 ± 0.3 12.5 ±3.1 13.2 ± 3   14.2 ± 3   (79.3) (83.1) (77.4) (79)   (78)   5h 4-OCH₃10 15.8 ± 0.9 27.4 ± 0.4 32.3 ± 0.3 35.1 ± 0.8 36.7 ± 0.4 (24)   (18.9)(41.6) (44.3) (43.1) 5i 3,4,5-(OCH₃)₃ 10 19.4 ± 0.4 22.3 ± 0.1 33.7 ±1.9 36.1 ± 0.1 37.1 ± 0.8  (6.7) (34)   (39.1) (42.7) (42.5) 5j 4-COOH10 10.3 ± 0.6 18 ± 1 24.2 ± 2.3 26.3 ± 0.7 27.5 ± 0.9 (50.5) (46.7)(56.2) (58.3) (57.4) 5k 4-F 10 11.2 ± 1.5 27.9 ± 2.5 33.9 ± 1.8 35.6 ±0.6  36.3 ± 0.02 (46.2) (17.5) (38.7) (43.5) (43.7) ^(a)Each valuerepresents the mean ± S.D. of 5 animals. ^(b)The number in parenthesesindicates the percentage inhibition rate (1%).

In the present invention, a compound with the following general formula(I) is disclosed,

wherein R is —H, 2-Cl, 3-Cl, 4-Cl, 2,4-(Cl)₂, 2-F, 3-F, 4-F, 2,4-(F)₂,2-Br, 3-Br, 4-Br, 2,4-(Br)₂, 2-CF₃, 3-CF₃, 4-CF₃, 2,4-(CF₃)₂, 2-COOH,3-COOH, 4-COOH, 2,4-(COOH)₂, 2-OCH₃, 3-OCH₃, 4-OCH₃, 3,4,5-(OCH₃)₃,2-NH—CO—CH₂Cl, 4-NH—CO—CH₂Cl, 2-NH—CO—CH₂Br, or 4-NH—CO—CH₂Br.

Also disclosed is a physiological tolerable salt of the compound of theformula (I).

The present invention also relates to a pharmaceutical compositioncomprising an effective amount of at least one compound of the formula(I) and/or a physiologically tolerable salt of the compound of theformula (I), in addition to pharmaceutically suitable excipients,additives, and/or active compounds and auxiliaries.

Examples of suitable forms of the pharmaceutical composition aretablets, coated tablets, injectable solutions, suspensions, emulsions,powders, granules, (micro)capsules, suppositories, and syrups.

Also disclosed in the present invention is a method comprising treatingrheumatoid arthritis by administering to a patient an effective amountof the pharmaceutical composition described above.

Also disclosed is a method of treating rheumatoid arthritis comprisingadministering to a patient the pharmaceutical composition and one of thedrugs on the market already used to treat rheumatoid arthritiscomprising dexamethasone, ibuprofen, leflunomide, malononitrilamide,diclofenac sodium, diclofenac potassium, naproxen, or naproxen sodium.

SUMMARY, RAMIFICATION, AND SCOPE

In conclusion, the present invention discloses a series of novel analogsof leflunomide for treating rheumatoid arthritis. The results of animalstudies indicate these analogs are surprisingly effective for treatingrheumatoid arthritis. Also disclosed in the present invention is amethod of treating rheumatoid arthritis, which comprises administeringto a patient a therapeutically effective amount of a pharmaceuticalcomposition comprising the analog.

Although the description above contains many specificities, these shouldnot be construed as limiting the scope of the invention but as merelyproviding the illustrations of some of the presently preferredembodiments of this invention. Thus the scope of this invention shouldbe determined by the appended claims and their legal equivalents, ratherthan by the examples given.

What is claimed is:
 1. A compound of the formula (I)

or a physiological tolerable salt of the compound of the formula (I),wherein R is —H, 2-Cl, 3-Cl, 4-Cl, 2,4-(Cl)₂, 2-F, 3-F, 4-F, 2,4-(F)₂,2-Br, 3-Br, 4-Br, 2,4-(Br)₂, 3-CF₃, 4CF₃, 2,4-(CF₃)₂, 2-COOH, 3-COOH,4-COOH, 2,4-(COOH)₂, 3-OCH₃, 4-OCH₃, 3,4,5-(OCH₃)₃, 2-NH—CO—CH₂Cl,4-NH—CO—CH₂Cl, 2-NH—CO—CH₂Br, or 4-NH—CO—CH₂Br.
 2. A pharmaceuticalcomposition comprising a compound of the formula (I)

or a physiological tolerable salt of the compound of the formula (I),wherein R is —H, 2-Cl, 3-Cl, 4-Cl, 2,4-(Cl)₂, 2-F, 3-F, 4-F, 2,4-(F)₂,2-Br, 3-Br, 4-Br, 2,4-(Br)₂, 3-CF₃, 4-CF₃, 2,4-(CF₃)₂, 2-COOH, 3-COOH,4-COOH, 2,4-(COOH)₂, 3-OCH₃, 4-OCH₃, 3,4,5-(OCH₃)₃, 2-NH—CO—CH₂Cl,4-NH—CO—CH₂Cl, 2-NH—CO—CH₂Br, or 4-NH—CO—CH₂Br.
 3. A method of treatingrheumatoid arthritis comprising administering to a patient an effectiveamount of a pharmaceutical composition comprising a compound of theformula (I)

or a physiological tolerable salt of the compound of the formula (I),wherein R is —H, 2-Cl, 3-Cl, 4-Cl, 2,4-(Cl)₂, 2-F, 3-F, 4-F, 2,4-(F)₂,2-Br, 3-Br, 4-Br, 2,4-(Br)₂, 2-CF₃, 3-CF₃, 4-CF₃, 2,4-(CF₃)₂, 2-COOH,3-COOH, 4-COOH, 2,4-(COOH)₂, 2-OCH₃, 3-OCH₃, 4-OCH₃, 3,4,5-(OCH₃)₃,2-NH—CO—CH₂Cl, 4-NH—CO—CH₂Cl, 2-NH—CO—CH₂Br, or 4-NH—CO—CH₂Br.
 4. Amethod of treating rheumatoid arthritis comprising administering to apatient a therapeutically effective amount of a composition comprising acompound of the formula (I)

or a physiological tolerable salt of the compound of the formula (I),wherein R is —H, 2-Cl, 3-Cl, 4-Cl, 2,4-(Cl)₂, 2-F, 3-F, 4-F, 2,4-(F)₂,2-Br, 3-Br, 4-Br,2,4-(Br)₂, 2-CF₃, 3-CF₃, 4-CF₃, 2,4-(CF₃)₂, 2-COOH,3-COOH, 4-COOH, 2,4-(COOH)₂, 2-OCH₃, 3-OCH₃, 4-OCH₃, 3,4,5-(OCH₃)₃,2-NH—CO—CH₂Cl, 4-NH—CO—CH₂Cl, 2-NH—CO—CH₂Br, or 4-NH—CO—CH₂Br, and adrug selected from the group consisting of dexamethasone, ibuprofen,leflunomide, malononitrilamide, diclofenac sodium, diclofenac potassium,naproxen, naproxen sodium, and combinations thereof.
 5. The compound ofclaim 1 wherein R is H, 2-Cl, 3-Cl, 4-Cl, 3-CF₃, 4-CF₃, 2,4-(Cl)₂,4-OCH₃, 3,4,5-(OCH₃)₃, 4-COOH, or 4-F.
 6. The compound of claim 1wherein R is H, 2-Cl, 3-Cl, 4-Cl, 4-CF₃, 2,4-(Cl)₂, 4-COOH, or 4-F. 7.The compound of claim 1 wherein R is 2-Cl, 4-Cl, or 2,4-(Cl)₂.
 8. Thecompound of claim 1 wherein R is 2-Cl.
 9. The compound of claim 1wherein R is 4-Cl.
 10. The compound of claim 1 wherein R is 2,4-(Cl)₂.11. The pharmaceutical composition of claim 2 wherein R is H, 2-Cl,3-Cl, 4-Cl, 3-CF₃, 4-CF₃, 2,4-(Cl)₂, 4-OCH₃, 3,4,5-(OCH₃)₃, 4-COOH, or4-F.
 12. The pharmaceutical composition of claim 2 wherein R is H, 2-Cl,3-Cl, 4-Cl, 4-CF₃, 2,4-(Cl)₂, 4-COOH, or 4-F.
 13. The pharmaceuticalcomposition of claim 2 wherein R is 2-Cl, 4-Cl, or 2,4-(Cl)₂.
 14. Thepharmaceutical composition of claim 2 wherein R is 2-Cl.
 15. Thepharmaceutical composition of claim 2 wherein R is 4-Cl.
 16. Thepharmaceutical composition of claim 2 wherein R is 2,4-(Cl)₂.
 17. Themethod of claim 3 wherein R is H, 2-Cl, 3-Cl, 4-Cl, 3-CF₃, 4-CF₃,2,4-(Cl)₂, 4-OCH₃, 3,4,5-(OCH₃)₃, 4-COOH, or 4-F.
 18. The method ofclaim 3 wherein R is H, 2-Cl, 3-Cl, 4-Cl, 4-CF₃, 2,4-(Cl)₂, 4-COOH, or4-F.
 19. The method of claim 3 wherein R is 2-Cl, 4-Cl, or 2,4-(Cl)₂.20. The method of claim 3 wherein R is 2-Cl.
 21. The method of claim 3wherein R is 4-Cl.
 22. The method of claim 3 wherein R is 2,4-(Cl)₂. 23.The method of claim 4 wherein R is H, 2-Cl, 3-Cl, 4-Cl, 3-CF₃, 4-CF₃,2,4-(Cl)₂, 4-OCH₃, 3,4,5-(OCH₃)₃, 4-COOH, or 4-F.
 24. The method ofclaim 4 wherein R is H, 2-Cl, 3-Cl, 4-Cl, 4-CF₃, 2,4-(Cl)₂, 4-COOH, or4-F.
 25. The method of claim 4 wherein R is 2-Cl, 4-Cl, or 2,4-(Cl)₂.26. The method of claim 4 wherein R is 2-Cl.
 27. The method of claim 4wherein R is 4-Cl.
 28. The method of claim 4 wherein R is 2,4-(Cl)₂.